Azacitidine-treated Patients Research Articles

Postazacitidine clone size predicts long-term outcome of patients with myelodysplastic syndromes and related myeloid neoplasms.

Azacitidine is a mainstay of therapy for myelodysplastic syndrome (MDS)-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their posttreatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pretreatment (n= 449) and posttreatment (n= 289) bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their posttreatment clone size on treatment outcomes. In Cox proportional hazard modeling, multihit TP53 mutation (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.42-2.91; P< .001), EZH2 mutation (HR, 1.71; 95%CI, 1.14-2.54; P= .009), and DDX41 mutation (HR, 0.33; 95%CI, 0.17-0.62; P< .001), together with age, high-risk karyotypes, low platelets, and high blast counts, independently predicted OS. Posttreatment clone size accounting for all drivers significantly correlated with International Working Group (IWG) response (P< .001, using trend test), except for that of DDX41-mutated clones, which did not predict IWG response. Combined, IWG response and posttreatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, the molecular International Prognostic Scoring System (IPSS-M; c-index, 0.653 vs 0.688; P< .001, using likelihood ratio test). In conclusion, evaluation of posttreatment clone size, together with the pretreatment mutational profile as well as the IWG response play a role in better prognostication of azacitidine-treated patients with myelodysplasia.

Fetal hemoglobin level predicts lower-risk myelodysplastic syndrome.

The relationship between fetal hemoglobin (HbF) levels and disease prognosis in patients with myelodysplastic syndrome (MDS) is unclear. This study aimed to clarify the relationship between HbF level and the prognosis of MDS. To this end, data from 217 patients diagnosed with MDS between April 2006 and August 2020 at Ebina General Hospital were analyzed retrospectively. The primary endpoint was leukemia-free survival (LFS) for 5years after diagnosis. HbF levels were significantly higher in patients with MDS than in control patients without MDS (n = 155), with a cut-off value of 0.4%. Higher-risk patients had a similar prognosis regardless of HbF level, but lower-risk patients had longer LFS at intermediate HbF levels. Although prognosis based on pre-treatment HbF levels did not differ significantly among azacitidine-treated patients, prognosis tended to be better in lower-risk patients with intermediate HbF levels. Multivariate analysis showed that the intermediate HbF category correlated with LFS, independently of MDS lower-risk prognostic scoring system (LR-PSS)-related factors. This study is the first to assess the association between HbF levels and the new World Health Organization 2016 criteria for MDS, demonstrating the significance of HbF levels in the prognosis of MDS.

Noncoding RNAs and Their Response Predictive Value in Azacitidine-treated Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia With Myelodysplasia-related Changes.

Prediction of response to azacitidine (AZA) treatment is an important challenge in hematooncology. In addition to protein coding genes (PCGs), AZA efficiency is influenced by various noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs), and transposable elements (TEs). RNA sequencing was performed in patients with myelodysplastic syndromes or acute myeloid leukemia before AZA treatment to assess contribution of ncRNAs to AZA mechanisms and propose novel disease prediction biomarkers. Our analyses showed that lncRNAs had the strongest predictive potential. The combined set of the best predictors included 14 lncRNAs, and only four PCGs, one circRNA, and no TEs. Epigenetic regulation and recombinational repair were suggested as crucial for AZA response, and network modeling defined three deregulated lncRNAs (CTC-482H14.5, RP11-419K12.2, and RP11-736I24.4) associated with these processes. The expression of various ncRNAs can influence the effect of AZA and new ncRNA-based predictive biomarkers can be defined.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

The Impact of the Epigenetic Cancer Drug Azacitidine on Host Immunity: The Role of Myelosuppression, Iron Overload and tp53 Mutations in a Zebrafish Model.

The unsatisfactory real-world efficacy of the hypomethylating agent azacitidine in treating myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) has prompted us to investigate the hematological adverse events and host variables that may compromise the use of this epigenetic drug. Using the zebrafish, we found that azacitidine destroyed their myeloid precursors and impaired myeloid function by inhibiting antigen processing, allogeneic response and phagocytic activity, resulting in increased susceptibility to infection even by the normal flora E. coli. In addition, iron overload, a MDS-associated condition following repeated transfusions, exacerbated bacterial infection especially by V. vulnificus with known iron dependence. Furthermore, we show that the tp53M214K mutant zebrafish survived longer than the wild-type (WT) when challenged with bacteria following azacitidine treatment. This was attributed to the mutant’s hematopoietic cells rather than its general genetic background, since the WT animals reconstituted with the tp53M214K mutant kidney marrow became more resistant to bacterial infection following treatment with azacitidine. The clinical relevance of our findings was indicated by a MDS case with severe azacitidine-induced bone marrow suppression and by the association of hyperferritinemia with bacteremia in azacitidine-treated patients, while tp53M214K-mediated resistance to azacitidine-induced myelosuppression may explain the survival advantage of malignant MDS and AML clones over their normal counterparts under azacitidine treatment. Together, we propose that myelosuppression, iron overload and TP53 mutations may represent the host variables that compromise the azacitidine efficacy.

New FDA Approved Therapies for AML &amp; Impact on the Older Population

New FDA Approved Therapies for AML &amp; Impact on the Older Population

Relationship between Altered Gene Expression and DNA Methylation of the DLK1-DIO3 region in Azacitidine-Treated Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

INTRODUCTIONMyelodysplastic syndromes (MDS) represent a heterogeneous spectrum of hematopoietic stem cell disorders characterized by inefficient hematopoiesis, peripheral blood cytopenia, dysplasia in one or more myeloid cell lineages, and a tendency to evolve into acute myeloid leukemia (AML). Hypomethylating agent azacitidine (AZA) is a standard therapy for patients with higher-risk MDS and AML with myelodysplasia-related changes (AML-MRC).The DLK1-DIO3 region is located on chromosome 14q32 and contains one of the largest miRNA clusters in the genome. Functions of these miRNAs have been linked to apoptosis and proliferation. Their expression is under the control of a differentially methylated region (DMR) located in the promoter of MEG3 gene. Significant overexpression of these miRNAs has previously been found in MDS and acute promyelocytic leukemia (APL). In APL, this upregulation has been linked to hypermethylation of MEG3-DMR. AIMSWe examined (i) expression of the 14q32 miRNAs and mRNAs (DLK1, RTL1, DIO3, MEG3, and MEG8) and (ii) DNA methylation of MEG3-DMR in patients with higher-risk MDS and AML-MRC before and during AZA treatment with the aim to reveal whether the overexpression of these miRNAs is epigenetically regulated in myelodysplasia. METHODSThe study comprised 24 paired samples of CD34+ bone marrow cells obtained from 12 patients with higher-risk MDS and AML-MRC before and during AZA therapy. miRNA profiling was done using Agilent microarrays and mRNA levels of the genes located within the 14q32 region were assessed by Illumina microarrays. Measurement of MEG3 level by RT-qPCR confirmed the microarray results on an independent cohort (81 MDS and 14 AML-MRC patients, and 13 controls). Methylation status of MEG3 promoter was investigated by amplicon bisulfite sequencing. RESULTSWe studied levels of miRNAs and mRNAs encoded in the DLK1-DIO3 region and found that 50 % of untreated patients showed strong upregulation of expression activity within the locus. Following AZA therapy, we observed a significant reduction in the miRNA/mRNA expression to nearly normal levels, suggesting that expression activity might be affected by hypomethylation. Interestingly, expression levels of miRNAs and mRNAs positively correlated, indicating that transcriptional activity was regulated uniformly throughout the region.Evaluation of expression data with clinical features in the pretreatment samples revealed that expression activity was related to BM blast count, patient diagnosis, and outcome. High expression was significantly associated with the diagnosis of AML-MRC and poor outcome, whereas low expression with MDS and favorable outcome. No chromosomal abnormality or cytogenetic risk category was linked to the expression changes.In the patients before treatment, we revealed a significant hypermethylation of a part of the MEG3-DMR that closely preceded the MEG3 start codon. This hypermethylation was seen in 50 % of the patients and negatively correlated with expression activity. Interestingly, the hypermethylation was associated with longer progression-free survival after initiation of AZA therapy (hazard ratio = 0.220, P = 0.03).Following AZA therapy, we identified an apparent decrease of methylation in another part of MEG3-DMR. This hypomethylation might be attributed to the hypomethylating effect of AZA and could therefore influence the deregulated expression of the miRNA cluster.Finally, we investigated the potential application of the deregulation observed in this locus for prognostic purposes regarding the responsiveness to AZA treatment. Although, we identified changes in expression and methylation levels before AZA therapy, these changes were not associated with future response status. CONLUSIONSHere, we correlated changes in expression of 14q32 miRNAs and mRNAs with specific methylation changes in its regulatory sequences in higher-risk MDS and AML-MRC patients treated with AZA. We thoroughly investigated a complex regulatory mechanism within this region and based on our data, we assumed that epigenetic alterations affect expression activity in the locus. However, also other mechanisms such as influence of some transcription factors may play yet unrecognized roles in the resulting state.Supported by grants 17-31398A, 16-33617A, 16-33485A, and 00023736 (Ministry of Health of the Czech Republic). DisclosuresNo relevant conflicts of interest to declare.

Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care

Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m2/day x7 days (n = 240) or conventional care regimens (CCR; n = 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51–0.99]; P = 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31–46% reduced risk of death vs CCR. The most frequent gene mutations were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140, 15%; R172, 8%]), and TP53 (21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with TP53 or NRAS mutations and azacitidine-treated patients with FLT3 or TET2 mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.

Relationship between Altered miRNA Expression and DNA Methylation of the DLK1-DIO3 Region in Azacitidine-Treated Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Myelodysplasia-Related Changes.

The DLK1–DIO3 region contains a large miRNA cluster, the overexpression of which has previously been associated with myelodysplastic syndromes (MDS). To reveal whether this overexpression is epigenetically regulated, we performed an integrative analysis of miRNA/mRNA expression and DNA methylation of the regulatory sequences in the region (promoter of the MEG3 gene) in CD34+ bone marrow cells from the patients with higher-risk MDS and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), before and during hypomethylating therapy with azacytidine (AZA). Before treatment, 50% of patients showed significant miRNA/mRNA overexpression in conjunction with a diagnosis of AML-MRC. Importantly, increased level of MEG3 was associated with poor outcome. After AZA treatment, the expression levels were reduced and were closer to those seen in the healthy controls. In half of the patients, we observed significant hypermethylation in a region preceding the MEG3 gene that negatively correlated with expression. Interestingly, this hypermethylation (when found before treatment) was associated with longer progression-free survival after therapy initiation. However, neither expression nor methylation status were associated with future responsiveness to AZA treatment. In conclusion, we correlated expression and methylation changes in the DLK1–DIO3 region, and we propose a complex model for regulation of this region in myelodysplasia.

The impact of antimicrobial prophylaxis in morbidity and infections during azacitidine treatment.

The clinical consequences of the infectious events in patients receiving azacitidine are poorly documented. Likewise, the role of primary antimicrobial prophylaxis is unknown. In this retrospective, single-center study, we compare the impact of prophylaxis on the incidence of infection and morbidity in all consecutive higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients, during the first 4 azacitidine cycles. Seventy-six patients, corresponding to 283 azacitidine cycles, were studied. There were infectious events in 43% of the patients. Development of infections led to more hospital admissions, increased red blood cells and platelet requirements, and a delay in subsequent cycles. Median overall survival was comparable between patients with or without infections. In the multivariate analysis, a neutrophil count below 0.5×109/L (OR 12.5 [2.6-50]) and antimicrobial prophylaxis (OR 0.1 [0.02-04]) were independent factors for the development of infection. We conclude that infectious events have a significant impact in the early clinical course of azacitidine-treated patients by increasing hospital admissions and transfusion requirements. Antimicrobial prophylaxis may prevent infections, leading to a decreased need for supportive care in these patients with poor outcome.

Treatment Patterns and Outcomes Among Patients with Higher-Risk Myelodysplastic Syndromes Treated in a Real-World Setting: Electronic Medical Record-Based Data

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders resulting in ineffective hematopoiesis primarily affecting older adults; median age of diagnosis is >70 years. Treatment decisions in MDS are largely based on a prognostic scoring system that has been incorporated into some drug labeling (NCCN 2016). The use of hypomethylating agents (HMAs) in patients with higher-risk (HR) MDS is supported by consensus guidelines, thus the purpose of this study was to examine factors influencing prescribing patterns in this subset of patients.Methods: This was a retrospective cohort study using a large United States electronic medical record database. Newly diagnosed HR MDS patients initiating first-line therapy (1LT) between 1/2008 and 7/2015 were followed for 1 year prior to and ≥ 60 days after diagnosis. Included patients were ≥18 years old with evidence of HR MDS identified as follows: 1) ≥1 inpatient claim with an HR MDS diagnosis code (ICD-9 code: 238.73; ICD-10 codes: D46.20, D46.21, D46.22), or 2) ≥2 outpatient claims with an MDS diagnosis code, with the first one coded for HR MDS ≥60 days but <1 year apart during the identification period. The date of the first HR MDS claim served as the index diagnosis date. 1LT was defined as an MDS-specific systemic agent initiated on or after the index diagnosis date and included all agents received within 30 days following the first infusion or fill date. Subsequent lines of therapy (LOT) were defined as an addition of a new MDS-specific agent >30 days after the initial chemotherapy agent(s) or a switch to another drug combination. Stem cell transplantation (SCT) was considered part of the LOT in which it occurred. All patients were followed until death or progression to acute myeloid leukemia (AML), loss to follow-up, or the end of study period (9/30/2015).Results: 345 patients newly diagnosed with HR MDS met the study criteria; 218 (63%) were treated with supportive care (including transfusions, hydroxyurea, colony-stimulating factors [CSFs], azole antifungals, erythropoiesis-stimulating agents [ESAs], or pain medications) or observation only and 127 (37%) were treated with MDS-directed therapy (HMAs, immunosuppressive therapy, induction-type therapy, SCT, or lenalidomide) ± supportive care (Table 1). Compared to untreated patients, a greater proportion of treated patients were male, had severe cytopenias (specifically, neutrophils <0.8 K/L and/or platelets <50 K/L), and had received a transfusion of either red blood cells or platelets during the baseline period (Table 1). In the treated population, most patients received only 1LT (n=111, 87%); 16 patients (13%) went on to second-line therapy, and 3 (2.3%) to third-line therapy. HMAs were the most utilized agents in 1LT, with 84 (66%) and 29 (23%) patients receiving azacitidine and decitabine, respectively. Lenalidomide was used in 6.3% of patients (n=8), and induction-type chemotherapy in 3.2% (n=4); no patients received immunosuppressive therapy only (cyclosporine or anti-thymocyte globulin). At median follow-up of 9 months (interquartile range [IQR]: 4, 16) for the treated population, 46 (36%) had died and 36 (28%) had progressed to AML. Within the population that received an HMA (n=113), age ≥75 years was approximately 50% for each agent; however, a greater proportion of patients who received azacitidine had a known marrow blast count of >5%, hemoglobin <10 gm/dL, and platelets <50 K/L at baseline (Table 2). At end of follow-up, 27% (n=23) and 36% (n=30) of azacitidine-treated patients had progressed to AML or died whereas 28% (n=8) and 41% (n=12) of decitabine-treated patients progressed to AML or died, respectively.Conclusions: Despite the existence of treatment guidelines for HR MDS patients and given the limitations of a retrospective study, the majority of patients in a real-world setting are not treated with MDS-specific agents. Younger age (<75 years) and more severe cytopenias may be factors considered in the decision of whether or not to treat HR MDS. If treated, HMAs are the most utilized therapy in these patients, with azacitidine predominating. Cytopenias at baseline may also influence the choice between azacitidine and decitabine, although survival and progression to AML appear similar between groups.

Response to treatment with azacitidine in children with advanced myelodysplastic syndrome prior to hematopoietic stem cell transplantation.

Advanced myelodysplastic syndrome harbors a high risk of progression to acute myeloid leukemia and poor prognosis. In children, there is no established treatment to prevent or delay progression to leukemia prior to hematopoietic stem cell transplantation. Azacitidine is a hypomethylating agent, which was shown to slow progression to leukemia in adults with myelodysplastic syndrome. There is little data on the efficacy of azacitidine in children. We reviewed 22 pediatric patients with advanced myelodysplastic syndrome from a single center, diagnosed between January 2000 and December 2015. Of those, eight patients received off-label azacitidine before hematopoietic stem cell transplantation. A total of 31 cycles were administered and modification or delay occurred in four of them due to cytopenias, infection, nausea/vomiting, and transient renal impairment. Bone marrow blast percentages in azacitidine-treated patients decreased significantly from a median of 15% (range 9-31%) at the start of treatment to 5.5% (0-12%, P=0.02) before hematopoietic stem cell transplantation. Following azacitidine treatment, four patients (50%) achieved marrow remission, and none progressed. In contrast, three untreated patients (21.4%) had progressive disease characterized by >50% increase in blast counts or progression to leukemia. Azacitidine-treated patients had significantly increased 4-year event-free survival (P=0.04); predicted 4-year overall survival was 100% versus 69.3% in untreated patients (P=0.1). In summary, azacitidine treatment prior to hematopoietic stem cell transplantation was well tolerated in pediatric patients with advanced myelodysplastic syndrome, led to partial or complete bone marrow response in seven of eight patients (87.5%), and correlated with superior event-free survival in this cohort.

Tracking the Somatic Mutations in Azacitidine-Treated MDS Patients Documents Clonal Development and AZA Responsiveness

Abstract Introduction and hypothesis: Somatic gene mutations develop in ~78% Myelodysplastic syndrome (MDS) patients. MDS progresses into an unstable phase characterized by an accumulation of myeloblasts that is indicated for the DNA demethylation therapy with Azacitidine (AZA). To understand whether AZA is capable to eliminate tumor cells and whether a mutation pattern responds to AZA we herein tracked mutations in the bone marrow (BM) during AZA treatment. Two scenarios were postulated: 1) AZA treatment will/ will not eliminate clones characterized by specific mutations and this will relate to the clinical outcome, 2) during clinical progression on the AZA treatment either the new mutations will develop or the original mutations will be detected. Patients: 40 int-2/high-risk MDS patients (176 samples, median age 70, 22F/18M) indicated for AZA (75mg/m2, 5+2+2) were sequenced. The MDS subtypes included RAEB1, RAEB2, and MDS/AML. Half of the patients progressed from the 5q-syndrome. Libraries were prepared using TruSight DNA amplicon kit. Set of 54 myeloid genes (associated with MDS or AML) were sequenced by Illumina platform HiSeq 2500 with depth &gt;100 per mutation, mutation should be heterozygous, non-synonymous, exonic with frequency &gt;10%. As controls: 4 normal BM samples and 2 cord bloods (also applied for data filtering) and MOLM-13 cell line carrying FLT3-ITD mutation were used. Additional controls included CD3+ T cells isolated from the patient BM samples. Results: 70% of patients were informative for at least one somatic mutation with high impact on the amino acid sequence. Mutations in TET2 (in 13%) were overall the most frequent before AZA was started (followed by mutations in BCOR, RUNX1, STAG2, and NOTCH genes). In 36% of informative patients, the mutation pattern developed on AZA. Interestingly, the most frequent mutations after AZA were in ASXL1 in 10% (followed by mutations in TET2, BCOR, and CUX1 genes). While mutations in ASXL1 and NOTCH genes developped only in the non-5q derived patients, the mutations in RUNX1 developped only in the 5q-derived higher-risk MDS patients. Average number of mutations before AZA and on AZA was 2 per patient. Complete elimination of the mutation pattern was noted in 57% of informative patients during the first 8 months of AZA treatment and this was associated with the therapy responsiveness (PR or CR). In contrast in 7% of informative patients the mutation pattern remained the same and this was associated with the stable disease (leading to progression). Upon progression on the AZA treatment we have observed appearance of the new mutations in 73% of informative patients. 20% of patients progressing after 14 cycles of AZA were non-informative which suggests that these patients may carry mutations in genes not included within the tested set. We have assessed overall survival (OS) according to the mutation status in the following subgroups: non-informative patients, informative patients with mutations that were eliminated by AZA, and those retaining or gaining the mutations upon AZA. The group that developed or retained mutations during first 4-8 cycles of AZA displayed significantly lower OS (p=0.004, median OS:11 months) compared to either non-informative patients (26 months) or those where AZA completely eliminated the mutation pattern (28 months). Conclusions: Tracking the mutations in MDS patients during AZA therapy provides opportunity to detect clonal development in 2/3 of the MDS patients and relate these data to the clinical outcome. Moreover, progression on AZA therapy is usually associated with the development of a new mutation pattern and this coincides with the significantly lower OS. Grants: GACR P305/12/1033, UNCE 204021, PRVOUK-P24/LF1/1. Disclosures Stopka: Celgene: Research Funding.

Effectiveness of azacitidine in unselected high-risk myelodysplastic syndromes: results from the Spanish registry

The benefit of azacitidine treatment in survival of high-risk myelodysplastic syndromes (MDS) patients compared with conventional care treatment (CCT) has not been established outside clinical trials. To assess its effectiveness, we compared overall survival (OS) between azacitidine and conventional treatment (CCT) in high-risk MDS patients, excluding those undergoing stem cell transplantation, submitted to the Spanish MDS registry from 2000 to 2013. Several Cox regression and competing risk models, considering azacitidine as a time-dependent covariate, were used to assess survival and acute myeloblastic leukemia (AML) progression. Among 821 patients included, 251 received azacitidine. Median survival was 13.4 (11.8-16) months for azacitidine-treated patients and 12.2 (11-14.1) for patients under CCT (P=0.41). In a multivariate model, age, International prognostic scoring system and lactate dehydrogenase were predictors of OS whereas azacitidine was not (adjusted odds ratio 1.08, 95% confidence interval 0.86-1.35, P=0.49). However, in patients with chromosome 7 abnormalities, a trend toward a better survival was observed in azacitidine-treated patients (median survival 13.3 (11-18) months) compared with CCT (median survival 8.6 (5-10.4) months, P=0.08). In conclusion, our data show that, in spite of a widespread use of azacitidine, there is a lack of improvement in survival over the years. Identification of predicting factors of response and survival is mandatory.

Comparison of the prognostic utility of the revised International Prognostic Scoring System and the French Prognostic Scoring System in azacitidine-treated patients with myelodysplastic syndromes.

The revised International Prognostic Scoring System (IPSS-R) was developed in a cohort of untreated myelodysplastic syndromes (MDS) patients. A French Prognostic Scoring System (FPSS) was recently reported to identify differential survival among azacitidine-treated patients with high-risk MDS. We applied the FPSS and IPSS-R to 150 patients previously randomized to azacitidine monotherapy or a combination of azacitidine with entinostat (a histone deacetylase inhibitor). Neither score predicted response but both discriminated patients with different overall survival (OS; median OS, FPSS: 9·7, 14·7, and 25·3 months, P = 0·018; IPSS-R: 12·5, 11·3, 20·8, and 36 months, P = 0·005). Statistical analysis suggested no improvement in OS prediction for the FPSS over the IPSS-R in azacitidine-treated patients.

A Jehovah's Witness with Acute Myeloid Leukemia Successfully Treated with an Epigenetic Drug, Azacitidine: A Clue for Development of Anti-AML Therapy Requiring Minimum Blood Transfusions.

Therapy for acute leukemia in Jehovah's Witnesses patients is very challenging because of their refusal to accept blood transfusions, a fundamental supportive therapy for this disease. These patients are often denied treatment for fear of treatment-related death. We present the first Jehovah's Witness patient with acute myeloid leukemia (AML) treated successfully with azacitidine. After achieving complete remission (CR) with one course of azacitidine therapy, the patient received conventional postremission chemotherapy and remained in CR. In the case of patients who accept blood transfusions, there are reports indicating the treatment of AML patients with azacitidine. In these reports, azacitidine therapy was less toxic, including hematoxicity, compared with conventional chemotherapy. The CR rate in azacitidine-treated patients was inadequate; however, some characteristics could be useful in predicting azacitidine responders. The present case is useful for treating Jehovah's Witnesses patients with AML and provides a clue for anti-AML therapy requiring minimum blood transfusions.

Azacitidine might be beneficial in a subgroup of older AML patients compared to intensive chemotherapy: a single centre retrospective study of 227 consecutive patients

BackgroundTreatment options in older acute myeloid leukaemia (AML) patients include intensive chemotherapy, best supportive care (BSC), and hypomethylating agents. Currently, limited data is available on hypomethylating agents in older AML patients in unselected patient populations.MethodsTo compare the effectiveness of azacitidine with conventional therapy, we collected data of 227 consecutive AML patients (≥60 years) who were treated with azacitidine (N = 26), intensive chemotherapy (N = 90), or BSC (N = 97).ResultsAzacitidine-treated patients were older and had more comorbidities, but lower white blood cell- and bone marrow blast counts compared with intensive chemotherapy patients. Complete or partial response was achieved in 42% of azacitidine-treated patients and in 73% of intensive chemotherapy patients (P = 0.005). However, the overall survival (OS) was similar (1-year-OS 57% versus 56%, P = 0.93; 2-year-OS 35% versus 35%, P = 0.92), and remained similar after correction for risk factors in a multivariate analysis. Patients treated with BSC had an inferior OS (1-year- and 2-year-OS 16% and 2%, P < 0.001). Compared to intensive chemotherapy, azacitidine-treated patients spent less days in the hospital (median in first three months 0.5 versus 56, P < 0.001), and needed less red blood cell and platelet transfusions (median per month 2.7 versus 7, P < 0.001 and 0.3 versus 5, P < 0.001) in the first three months.ConclusionsAzacitidine treatment is associated with a comparable OS but higher tolerability in a subgroup of older AML patients compared with intensive chemotherapy. Patients receiving BSC had a poor prognosis.

Azacitidine Prolongs Overall Survival Compared With Conventional Care Regimens in Elderly Patients With Low Bone Marrow Blast Count Acute Myeloid Leukemia

In a phase III randomized trial, azacitidine significantly prolonged overall survival (OS) compared with conventional care regimens (CCRs) in patients with intermediate-2- and high-risk myelodysplastic syndromes. Approximately one third of these patients were classified as having acute myeloid leukemia (AML) under current WHO criteria. This analysis compared the effects of azacitidine versus CCR on OS in this subgroup. Patients were randomly assigned to receive subcutaneous azacitidine 75 mg/m(2)/d or CCR (best supportive care [BSC] only, low-dose cytarabine (LDAC), or intensive chemotherapy [IC]). Of the 113 elderly patients (median age, 70 years) randomly assigned to receive azacitidine (n = 55) or CCR (n = 58; 47% BSC, 34% LDAC, 19% IC), 86% were considered unfit for IC. At a median follow-up of 20.1 months, median OS for azacitidine-treated patients was 24.5 months compared with 16.0 months for CCR-treated patients (hazard ratio = 0.47; 95% CI, 0.28 to 0.79; P = .005), and 2-year OS rates were 50% and 16%, respectively (P = .001). Two-year OS rates were higher with azacitidine versus CCR in patients considered unfit for IC (P = .0003). Azacitidine was associated with fewer total days in hospital (P < .0001) than CCR. In older adult patients with low marrow blast count (20% to 30%) WHO-defined AML, azacitidine significantly prolongs OS and significantly improves several patient morbidity measures compared with CCR.

Comparative Cost-Effectiveness of Azacitidine Versus Decitabine for the Treatment of Myelodysplastic Syndromes (MDS).

Abstract 1377Poster Board I-399 Introduction:National Comprehensive Cancer Network guidelines recommend the use of azacitidine and decitabine to treat patients with myelodysplastic syndromes (MDS). In a Phase III clinical trial (AZA-001), MDS patients treated with azacitidine experienced a statistically significant increase in overall survival compared to patients receiving conventional care (24.5 vs. 15.0 months, p<0.0001) (Fenaux 2009). In addition, fewer azacitidine-treated patients required blood transfusions, and use of azacitidine delayed progression to acute myelogenous leukemia (AML). While the clinical benefits of azacitidine have been demonstrated, no study has evaluated its cost-effectiveness relative to decitabine. Methods:We developed a dynamic decision-analytic model (Markov process with 1-month cycles) to evaluate the cost-effectiveness of azacitidine versus decitabine for the treatment of MDS patients. Model parameters were derived from published literature, product labels, clinical trial data, and drug pricing and medical services cost databases. While patient populations in the clinical trials referenced for this model differed (i.e., approximately 1/3 of patients in the decitabine clinical trial were classified as lower-risk MDS patients, whereas approximately 90% of the azacitidine trial patients were higher-risk) (Kantarjian 2006, Fenaux 2009), data from the two trials were the highest quality available. The model tracks hypothetical cohorts of 1,000 MDS patients treated with azacitidine or decitabine over time periods of 1 and 3 years. Patients either remain in or transition among 4 health states in the model: (1) MDS with transfusion dependence; (2) MDS with transfusion independence; (3) progression to AML; or (4) dead. Clinical and economic consequences of adverse events were not included in the model. Clinical outputs generated by the model include: (1) number of patients progressing to AML; (2) number of patient months with transfusion independence; and (3) quality-adjusted life months/years (QALMs/QALYs). The primary economic output was treatment cost (including drug acquisition, administration and monitoring, blood transfusions, and iron chelation therapy). Cost-effectiveness of azacitidine versus decitabine was measured incrementally as: (1) cost per QALY gained; (2) cost per additional patient month of transfusion independence; (3) cost per additional case of AML progression avoided. The model used a US third-party payer perspective. Costs are stated as 2009 US dollars. One-way sensitivity analyses were performed on key model parameters to assess robustness of results. Results:The total number of QALYs (per 1,000 patients) for azacitidine-treated patients exceeded those for decitabine-treated patients in both the 1-year scenario (579 vs. 526) and the 3-year scenario (1,446 vs. 1,175). The total number of patient months with transfusion independence was higher for azacitidine vs. decitabine in both the 1-year scenario (4,340 vs. 3,521) and the 3-year scenario (11,836 vs. 8,553). A greater number of azacitidine-treated patients avoided progression to AML compared to decitabine-treated patients in both the 1-year scenario (664 vs. 462) and the 3-year scenario (372 vs. 231). Total per-patient costs for azacitidine-treated patients were lower than for decitabine-treated patients in both the 1-year scenario ($29,921 vs. $43,208), and the 3-year scenario ($101,052 vs. $106,806). In the 1-year scenario, costs for an azacitidine-treated patient were $13,287 less than those for a decitabine-treated patient, and azacitidine conferred a benefit of 0.0526 additional QALYs. In the 3-year scenario, costs for an azacitidine-treated patient were $5,754 less than those for a decitabine-treated patient, and azacitidine conferred a benefit of 0.2707 additional QALYs. Thus, incremental cost-effectiveness ratios (ICERs) for both the 1-year and 3-year scenarios demonstrate that azacitidine consistently had lower cost and provided greater health benefit compared to decitabine across all outcomes of interest. Conclusion:Model results suggest that despite a higher-risk profile in the underlying data for azacitidine, treatment of MDS patients with azacitidine leads to cost savings—it costs less and confers greater clinical benefit than decitabine. These results accentuate azacitidine as a major asset in providing cost-effective care for MDS patients. Disclosures:Miller: Celgene Corporation: Consultancy. Fenaux: Celgene, Ortho Biotech, Roche, Novartis, Cephalon, Epicept, Amgen, Merck: Honoraria, Research Funding. Beach: Celgene Corporation: Employment. Gidwani: Celgene Corporation: Consultancy. Khan: Celgene Corporation: Employment.

Further Analysis of Trials With Azacitidine in Patients With Myelodysplastic Syndrome: Studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B

Within the last two decades, a new understanding of the biology of myelodysplastic syndrome (MDS) has developed. With this understanding, new classification systems, such as the WHO diagnostic criteria, and the International Prognostic Scoring System and response criteria guidelines reported by the International Working Group (IWG) have been developed. We report the combined results of three previously reported clinical trials (n = 309) with azacitidine using the WHO classification system for MDS and acute myeloid leukemia (AML) and IWG criteria for response. Data from three sequential Cancer and Leukemia Group B trials with azacitidine were recollected and reanalyzed as part of the New Drug Application process. The trials were conducted with either intravenous or subcutaneous azacitidine (75 mg/m2/d for 7 days every 28 days). Complete remissions were seen in 10% to 17% of azacitidine-treated patients; partial remissions were rare; 23% to 36% of patients had hematologic improvement (HI). The median number of cycles to first response was three, and 90% of responses were seen by cycle 6. Using current WHO criteria, 103 patients had AML at baseline; 35% to 48% had HI or better responses. The median survival time for the 27 AML patients randomly assigned to azacitidine was 19.3 months compared with 12.9 months for the 25 patients assigned to observation. Furthermore, azacitidine did not increase the rate of infection or bleeding above the rate caused by underlying disease. Azacitidine provides important clinical benefits for patients with high-risk MDS.